Thiazolides Elicit Anti-Viral Innate Immunity and Reduce HIV Replication

Abstract

Nitazoxanide (Alinia®, NTZ) and tizoxanide (TIZ), its active circulating metabolite, belong to a class of agents known as thiazolides (TZD) endowed with broad anti-infective activities. TIZ and RM-4848, the active metabolite of RM-5038, were shown to stimulate innate immunity in vitro. Because natural resistance to HIV-1 infection in HIV-exposed seronegative (HESN) individuals is suggested to be associated with strong innate immune responses, we verified whether TIZ and RM-4848 could reduce the in vitro infectiousness of HIV-1. Peripheral blood mononuclear cells (PBMCs) from 20 healthy donors were infected in vitro with HIV-1BaL in the presence/absence of TIZ or RM4848. HIV-1 p24 were measured at different timepoints. The immunomodulatory abilities of TZD were evaluated by the expression of type I IFN pathway genes and the production of cytokines and chemokines. TZD drastically inhibited in vitro HIV-1 replication (>87%). This was associated with the activation of innate immune responses and with the up-regulation of several interferon-stimulated genes (ISGs), including those involved in cholesterol pathway, particularly the cholesterol-25 hydroxylase (CH25H). TZD inhibition of HIV-1 replication in vitro could be due to their ability to stimulate potent and multifaceted antiviral immune responses. These data warrant the exploration of TZD as preventive/therapeutic agent in HIV infection.

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

“…Importantly, nitazoxanide is rapidly metabolised to tizoxanide in humans and this active metabolite is being investigated against SARS-CoV-2 (NCT04341493 and NCT04343248). Tizoxanide has been reported to exhibit similar activities to nitazoxanide for other viruses as well as other pathogens [43][44][45]. The mechanism of antiviral action is not fully understood for nitazoxanide, but it has been reported to affect viral genome synthesis, prevent viral entry and interfere with the N-glycosylation and maturation of the influenza hemagglutinin [46][47][48][49].…”

Inhibition of rubella virus replication by the broad-spectrum drug nitazoxanide in cell culture and in a patient with a primary immune deficiency

“…It is currently unclear whether the identified cellular mechanisms were responsible for the reduction of RV antigen in the patient lesions. For example, immunomodulatory effects of NTZ (Hong et al, 2012;Trabattoni et al, 2016) may have played a role. Following oral administration, NTZ is rapidly adsorbed in the gastrointestinal tract and then hydrolyzed to form tizoxanide (desacetyl nitazoxanide), which is further metabolized to form tizoxanide glucuronide (Broekhuysen et al, 2000).…”

“…NTZ targets host functions that are essential for viral replication, but are not pathogen-specific. Several anti-viral mechanisms have been proposed such as induction of innate immunity, downregulation of viral receptors or interference with maturation of viral structural proteins at the post-translational stage, probably due to Ca2+ depletion inducing chronic sub-lethal stress in the endoplasmic reticulum (ER) (Ashiru et al, 2014;Elazar et al, 2009;Gekonge et al, 2015;Korba et al, 2008;La Frazia et al, 2013;Rossignol et al, 2009;Trabattoni et al, 2016).…”

Influenza antivirals currently in late‐phase clinical trial

“…Some of these derivatives demonstrate improved bio‐availability compared to NTZ and were shown to stimulate innate immune responses to reduce HIV replication in vitro . One of the thialozide compounds, the amino ester prodrug derivative RM5061, is now undergoing Phase I clinical trials …”